{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:41:37Z","timestamp":1791312097200,"version":"4.3.1"},"reference-count":26,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2018,3,1]],"date-time":"2018-03-01T00:00:00Z","timestamp":1519862400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI116939"],"award-info":[{"award-number":["R01 AI116939"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Ceftazidime-avibactam (CAZ-AVI) is a promising novel treatment for infections caused by carbapenem-resistant\n            <jats:named-content content-type=\"genus-species\">Enterobacteriaceae<\/jats:named-content>\n            (CRE). Despite improved treatment outcomes compared to those achieved with aminoglycoside- and colistin-based regimens, the rapid evolution of CAZ-AVI resistance during treatment has previously been reported in\n            <jats:named-content content-type=\"genus-species\">Klebsiella pneumoniae<\/jats:named-content>\n            sequence type 258 (ST258)\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>KPC-3<\/jats:sub>\n            -harboring isolates. Here, we report the stepwise evolution and isolation of two phenotypically distinct CAZ-AVI-resistant\n            <jats:named-content content-type=\"genus-species\">Klebsiella pneumoniae<\/jats:named-content>\n            isolates from a patient with pancreatitis. All susceptible (\n            <jats:italic>n<\/jats:italic>\n            = 3) and resistant (\n            <jats:italic>n<\/jats:italic>\n            = 5) isolates were of the ST307 clonal background, a rapidly emerging clone. Taking advantage of short-read Illumina and long-read Oxford Nanopore sequencing and full-length assembly of the core chromosome and plasmids, we demonstrate that CAZ-AVI resistance first occurred through a 532G \u2192 T\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>KPC-2<\/jats:sub>\n            point mutation in\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>KPC-2<\/jats:sub>\n            (D179Y protein substitution) following only 12 days of CAZ-AVI exposure. While subsequent isolates exhibited substantially decreased meropenem (MEM) MICs (\u22642 \u03bcg\/ml), later cultures demonstrated a second CAZ-AVI resistance phenotype with a lower CAZ-AVI MIC (12 \u03bcg\/ml) but also MEM resistance (MIC &gt; 128 \u03bcg\/ml). These CAZ-AVI- and MEM-resistant isolates showed evidence of multiple genomic adaptations, mainly through insertions and deletions. This included amplification and transposition of wild-type\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>KPC-2<\/jats:sub>\n            into a novel plasmid, an IS\n            <jats:italic>1<\/jats:italic>\n            insertion upstream of\n            <jats:italic>ompK36<\/jats:italic>\n            , and disruption of the\n            <jats:italic>rfb<\/jats:italic>\n            gene locus in these isolates. Our findings illustrate the potential of CAZ-AVI resistance to emerge in non-\n            <jats:named-content content-type=\"genus-species\">K. pneumoniae<\/jats:named-content>\n            ST258 clonal backgrounds and alternative\n            <jats:italic>bla<\/jats:italic>\n            <jats:sub>KPC<\/jats:sub>\n            variants. These results raise concerns about the strong selective pressures incurred by novel carbapenemase inhibitors, such as avibactam, on isolates previously considered invulnerable to CAZ-AVI resistance. There is an urgent need to further characterize non-KPC-mediated modes of carbapenem resistance and the intrinsic bacterial factors that facilitate the rapid emergence of resistance during treatment.\n          <\/jats:p>","DOI":"10.1128\/aac.02101-17","type":"journal-article","created":{"date-parts":[[2017,12,18]],"date-time":"2017-12-18T15:11:27Z","timestamp":1513609887000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":196,"title":["Successive Emergence of Ceftazidime-Avibactam Resistance through Distinct Genomic Adaptations in\n            <i>bla<\/i>\n            <sub>KPC-2<\/sub>\n            -Harboring Klebsiella pneumoniae Sequence Type 307 Isolates"],"prefix":"10.1128","volume":"62","author":[{"given":"Marla J.","family":"Giddins","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA"},{"name":"Department of Medicine Microbiome &amp; Pathogen Genomics Core, Columbia University Medical Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nenad","family":"Macesic","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA"},{"name":"Department of Infectious Diseases, Austin Hospital, Heidelberg, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Medini K.","family":"Annavajhala","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA"},{"name":"Department of Medicine Microbiome &amp; Pathogen Genomics Core, Columbia University Medical Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephania","family":"Stump","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA"},{"name":"Department of Medicine Microbiome &amp; Pathogen Genomics Core, Columbia University Medical Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H.","family":"McConville","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Mehta","sequence":"additional","affiliation":[{"name":"New York Presbyterian Hospital, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Gomez-Simmonds","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Catrin","family":"Uhlemann","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA"},{"name":"Department of Medicine Microbiome &amp; Pathogen Genomics Core, Columbia University Medical Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw243"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(16)30004-4"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02097-16"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01165-15"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00537-17"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00989-17"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.102188799"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02534-16"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1099\/mgen.0.000073"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00678-15"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00489-17"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04406-14"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00163-15"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.03455-14"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00079-17"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1099\/mgen.0.000110"},{"key":"e_1_3_2_18_2","volume-title":"Document M100-S25","author":"Clinical and Laboratory Standards Institute","year":"2015","unstructured":"Clinical and Laboratory Standards Institute. 2015. Performance standards for antimicrobial susceptibility testing, 25th informational supplement. Document M100-S25. Clinical and Laboratory Standards Institute, Wayne, PA,"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-014-0090-6"},{"key":"e_1_3_2_20_2","unstructured":"Seemann T. 2017. Rapid haploid variant calling and core SNP phylogeny. https:\/\/github.com\/tseemann\/snippy. Accessed 15 August 2017."},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw387"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv401"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts199"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu555"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1089\/cmb.2012.0021"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu153"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.2289704"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02101-17","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02101-17","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T21:04:29Z","timestamp":1645477469000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.02101-17"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3]]},"references-count":26,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2018,3]]}},"alternative-id":["10.1128\/AAC.02101-17"],"URL":"https:\/\/doi.org\/10.1128\/aac.02101-17","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3]]},"assertion":[{"value":"2017-10-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-12-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-02-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02101-17"}}